H1-receptor antagonists terfenadine and loratadine inhibit spontaneous growth of neoplastic mast cells

Abstract

Objective-In mast cell (MC) neoplasms, clinical problems requiring therapy include i) the local aggressive and sometimes devastating growth of MC and ii) mediator-related symptoms. A key mediator of MC responsible for clinical symptoms is histamine. Therefore, the use of histamine receptor (HR) antagonists is an established approach to block histamine effects in these patients.Methods and Results-We screened for additional beneficial effects of HR antagonists and asked whether any of these agents would also exert growth-inhibitory effects on primary neoplastic MC, the human MC line HMC-1, and on two canine MC lines, C2 and NI-1. We found that the HR1 antagonists terfenadine and loratadine suppress spontaneous growth of HMC-1, C2, and NI-1 cells, as well as growth of primary neoplastic MC in all donors tested (human patients, n=5; canine patients, n=8). The effects of both drugs were found to be dose-dependent (IC 50 : terfenadine, 1-20 μM; loratadine, 10-50 μM). Both agents also produced apoptosis in neoplastic MC and augmented apoptosis-inducing effects of two KIT-targeting drugs, PKC412 and dasatinib. The other HR1 antagonists (fexofenadine, diphenhydramine) and HR2 antagonists (famotidine, cimetidine, ranitidine) tested did not exert substantial growth-inhibitory effects on neoplastic MC. None of the histamine receptor blockers were found to modulate cell cycle progression in neoplastic MC. Conclusions-The Europe PMC Funders Group Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts (terfenadine) alone or in combination with KIT-inhibitors, can also affect in vivo neoplastic MC growth remains to be determined.

Update on Diagnosis and Treatment of Mastocytosis

“…For prophylaxis of recurrent episodes of anaphylaxis or persistent pruritus, antihistamines should be administered daily. In vitro antihistamines have been shown to inhibit spontaneous growth of neoplastic mast cell lines [42]. Whether this also affects in vivo neoplastic mast cell growth remains to be determined.…”

Solid Lipid Nanoparticles and Nanostructured Lipid Carriers of Loratadine for Topical Application: Physicochemical Stability and Drug Penetration through Rat Skin

“…The second generation of H1 receptor blocking agents including loratadine (LRT), can be used for inhibiting histamine release from the basophilic granulocytes and the mastocytes where histamine is stored in tissues [3]. LRT displays various side effects including several allergic reactions including rash, hives, itching, difficulty in breathing, tightness in the chest, swelling of the mouth or face and dizziness during systemic administration by oral route.…”

Current treatment options in patients with mastocytosis: status in 2015 and future perspectives

“…Based on in vitro experiments, certain second‐generation H1R blockers, such as rupatadine, azelastine, epinastine, or olopatadine, may act not only by blocking histamine binding to its receptors, but also by inhibiting MC degranulation . Moreover, we have observed that the H1R antagonists terfenadine and loratadine suppress spontaneous growth of neoplastic MCs in vitro . However, such effects are observed at relatively high drug concentrations that might not be reachable in vivo .…”